Process for the preparation of cephalosporins

ABSTRACT

The present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I)

[0001] This application is a continuation in part of pending U.S.application Ser. No. 10/207,103 filed on Jul. 30, 2002.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for the preparation ofcephalosporin antibiotics of the formula (I)

[0003] wherein R₁ represents hydrogen, trityl, CH₃, CR_(a)R_(b)COOR_(c)where R_(a) and R_(b) independently represent hydrogen or methyl andR_(c) represents hydrogen or (C₁-C₆)alkyl; R₂ represents CH₃, CH₂OCH₃,CH₂OCOCH₃, CH═CH₂,

BACKGROUND OF THE INVENTION

[0004] EP 0030294 discloses a process for the preparation of compound ofcephalosporin antibiotic as given in scheme 1:

[0005] wherein R represents hydrogen atom or a readily hydrolysableester group and X represents one of the groups

[0006] EP patent 0 842 937 discloses a process for the preparation ofcompound of cephalosporin antibiotic as given in scheme 2:

[0007] wherein R is

[0008] WO 00/63214 discloses a process for the preparation ofcephalosporins by condensation of carboxy ester intermediate withsilylated thiourea.

[0009] wherein X and R₁ are substituents useful in cephalosporinchemistry and R_(E) is hydrogen, a negative charge or together with theCOO— group to which R_(E) is attached is an ester, Y is halogen; R′ ishydrogen or silyl and R″ is silyl; R′_(E) is silyl or together with theCOO— group to which R_(E) is attached is an ester.

[0010] This patent publication discloses an alternate process, whichinvolves the desilylation of compound of formula (II) and thencondensation of desilylated compound with thiourea.

[0011] WO 02/083634 discloses a process for the preparation ofcefpodoxime of formula (XII), as shown in scheme 3 below:

[0012] wherein R is hydrogen or silyl group and R′ is silyl group orCOOR′ is a carboxylic acid salt; X is halogen. The process comprisesreacting the compound of formula (IX) with compound of formula (III) anddesilylating the compound of formula (X) and cyclizing the desilylatedcompound with thiourea to produce cefpodoxime acid of formula (XII).

OBJECTIVES OF THE INVENTION

[0013] The primary objective of the invention is to provide a new methodfor the preparation of cephalosporin antibiotics of the formula (I),which would be easy to implement in commercial scales.

SUMMARY OF THE INVENTION

[0014] Accordingly, the present invention provides a process for thepreparation of cephalosporin antibiotics of the formula (I) or itsesters, which form prodrug or a counter ion which forms salt

[0015] wherein R₁ represents hydrogen, trityl, CH₃, CR_(a)R_(b)COOR_(c)where R_(a) and R_(b) independently represent hydrogen or methyl andR_(c) represents hydrogen or (C₁-C₆)alkyl; R₂ represents hydrogen, CH₃,CH₂OCH₃, CH₂OCOCH₃, CH═CH₂, CH₂OCONH₂,

[0016] which comprises:

[0017] (i) condensing the activated derivative of the formula (III)where X represents halogen atom such as chlorine or bromine, withsilylated derivative of 7-amino cephalosporin of the formula (XIII)wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl ordiphenylmethyl group in the presence of a solvent at a temperature inthe range of −50° C. to 0° C. to produce a compound of formula (XIV),where R is as defined earlier,

[0018] (ii) cyclising the compound of formula (XIV) with thiourea in thepresence of solvent and sodium acetate at room temperature to producecephalosporin compound of the formula (XV) wherein R is as definedearlier,

[0019] (iii) deesterifying the compound of formula (XV) usinganisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acidin the presence or absence of a solvent at a temperature in the range of0° C. to 60° C. to produce a compound of formula (I) and

[0020] (iv) converting the compound of formula (I), to itspharmaceutically acceptable salt or its esters which form prodrug.

[0021] The process is shown in Scheme-4 below

[0022] In yet another embodiment of the present invention, there isprovided a process for the preparation of compound of formula (XIII)

[0023] which comprises:

[0024] (i) reacting the 7-aminocephalosporin derivative of the formula(XVI) wherein R₃ represents hydrogen, (C₁-C₄)alkyl, substituted orunsubstituted phenyl or substituted or unsubstituted phenoxy with R₂—X,wherein X represents halogen atom and R₂ is as defined earlier in thepresence in an organic solvent and a base at a temperature in the rangeof 0° C. to 30° C. to produce 7-aminocephalosporin derivative of theformula (XVII),

[0025] (ii) deacylating the compound formula (XVII) usingPCl₅/POCl₃/pyridine, PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes inthe presence of an alcohol, at a temperature in the range of −40° C. to0° C. to produce a compound of the formula (XIII) and

[0026] (iii) isolating the compound of formula (XIII).

[0027] The process is shown in Scheme-5 below

[0028] In yet another embodiment of the present invention, there isprovided a process for the preparation of compound of formula (XIII)

[0029] which comprises:

[0030] (i) acylating the 7-aminocephalosporin derivative of the formula(XVIII) phenyl acetyl chloride to produce compound of formula (XIX) inthe presence of an organic solvent at a temperature in the range of −20°C. to 30° C.,

[0031] (ii) esterifying the compound of formula (XIX) using anesterifying agent in the presence of a solvent and a base at atemperature in the range of 25° C. to 50° C. to produce a compound offormula (XX)

[0032] (iii) deacylating the compound of formula (XX) usingPCl₅/POCl₃/pyridine, PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes inthe presence of an alcohol, at a temperature in the range of −40° C. to0° C. to produce a compound of the formula (XIII) and

[0033] (iv) isolating the compound of formula (XIII).

[0034] The process is shown in Scheme-6 below

[0035] In still another embodiment of the present invention the compoundof formula (XIII), can be prepared by a process, which comprisesesterifying the compound of the formula (XVIII) using an esterifyingagent in the presence of a solvent and base.

[0036] The process is as shown in Scheme-7 below

[0037] wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzylor diphenylmethyl group and R² is as defined above.

[0038] In another embodiment of the present invention, there is provideda new intermediate of the formula (XIV)

[0039] wherein X represents halogen atom such as chlorine or bromine; Rrepresents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R₂represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH═CH₂, CH₂OCONH₂,

DETAILED DESCRIPTION OF THE INVENTION

[0040] In yet another embodiment of the present invention, thecondensation of compound of formula (III) with (XIII) is performed byusing the activated derivative of formula (III) in the presence of asolvent selected from dichloromethane, ethyl acetate, tetrahydrofuran,aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc,N,N-dimethylformamide, dialkylethers, water or mixtures thereof.

[0041] The compound of formula (III) is activated as acid halides, mixedanhydrides, active esters, active amides. The acid halides are acidchlorides or acid bromides. The mixed anhydrides are anhydrides of thecompounds of formula (III) with pivaloyl chloride, ethyl chloroformate,benzyl chloroformate.

[0042] In yet another embodiment of the present invention, thesilylation of 7-amino cephalosporin of the formula (XIII) is carried outusing silylating agent selected from hexamethyldisilazane (HMDS),trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI),N,O-bis-(trimethylsilyl)-acetamide (BSA),methyltrimethylsilyltrifluoroacetamide (MSTFA),N,O-bistrimethylsilyltrifiuoroacetamide (BSTFA), methyldichlorosilane,dimethyldichlorosilane, diphenyldichlorosilane, N-methylsilylacetamide(MSA), bistrimethylsilylurea and the like.

[0043] In yet another embodiment of the present invention, thecyclisation of compound of (XIV) is carried out using solvents selectedfrom water, tetrahydrofuran, acetone, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C₁-C₃)alcoholand the like or mixtures thereof.

[0044] In still another embodiment of the present invention thedeesterification of compound of formula (XV) is carried out usinganisole/trifluoroacetic acid, phenol/trifluoroacetic acid, formic acidin the absence or presence of dichloromethane, dichloroethane as asolvent.

[0045] In another embodiment of the present invention, thepharmaceutically acceptable salt is sodium or hydrochloride.

[0046] In yet another embodiment of the present invention the prodrugester is proxetil, axetil, hexetil, pivoxil and the like.

[0047] In another embodiment of the present invention, the solvent usedfor reacting the compound of formula (XVI) in step (i) of scheme-5 isselected from tetrahydrofuran, acetone, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C₁-C₃)alcohol ormixtures thereof, in the presence of a base selected from sodiumacetate, potassium carbonate, triethylamine,1,4-diazabicyclo-[2,2,2]-octane (DABCO),1,5-diazabicyclo[4,3,0]-non-5-ene (DBN),1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.

[0048] In another embodiment of the present invention, the acylation ofcompound of formula (XVIII) in step (i) of scheme-6 is carried out inthe presence of solvent selected from toluene, xylene, benzene,methylene dichloride, chloroform, ethyl acetate and the like.

[0049] In another embodiment of the present invention, theesterification of compound of formula (XIX) in step (ii) of scheme-6 iscarried out using esterifying agents such as diphenyl diazomethane,alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride and asolvent selected from methylene dichloride, chloroform, ethyl acetate,toluene, water, tetrahydrofuran, acetone, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide N,N-dimethylacetamide,dioxane, (C₁-C₃)alcohol or mixtures thereof, in the presence ofcatalytic quantities of iodine. The reaction is carried out in thepresence of base such as sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate and the like.

[0050] In another embodiment of the present invention, the solvent usedfor reaction in scheme-7 is selected from tetrahydrofuran, acetone,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,(C₁-C₃)alcohol or mixtures thereof, in the presence of a base selectedfrom sodium acetate, potassium carbonate, triethylamine,1,4-diazabicyclo-[2,2,2]-octane (DABCO),1,5-diazabicyclo[4,3,0]-non-5-ene (DBN),1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.

[0051] The substituent on R₃ in Scheme-5 is selected from methyl,methoxy, nitro or halogen atom.

[0052] In yet another embodiment of the present invention, the productobtained in any of the reactions may be used in next step withoutisolation.

[0053] The present invention is provided by the examples below, whichare provided by way of illustration only and should not be considered tolimit the scope of the invention.

EXAMPLE-1

[0054] Step I

[0055] Preparation of7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic Acid

[0056] 7-Amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA) (100gm) was reacted with N,O-bis silyl acetamide (103.9 gm) in presence ofmethylene dichloride (300 mL) at RT for 1 hour under nitrogenatmosphere. The silylated mass was cooled to −10 to −15° C. To thisphenyl acetyl chloride (95 gm) was added over 30 minutes, and stirredfor 1 hour. After completion of the reaction, chilled water (1000 mL)was added at −10 to −15° C., distilled off methylene chloride undervacuum at 10-12° C. for 30 minutes. Filtered the product and washed withisopropyl ether (1000 mL) and dried under vacuum 40-45° C. till to getthe title compound (123 g, purity 95%).

[0057] Step II

[0058] Preparation of7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic Acid p-methoxyBenzyl Ester

[0059] p-Methoxy benzyl chloride (66 g) was stirred with sodium iodide(41.4 g) in presence of dimethyl sulfoxide (200 mL) for 1 hour at 25-30°C. To this 7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid(100 gm) obtained in step I and sodium bicarbonate (35.3 g) was addedand stirred for 25-30° C. for 5-7 hours. After completion of thereaction, the reaction mass was cooled to 20° C. and added DM water (2.5L) containing sodium thiosulphate (10 gm). The reaction mixture wasstirred for 30 min. at 25-30° C., filtered the product and washed withDM water (500 mL). Finally stirred the product with methanol (600 mL) at−5° C. and filtered, dried the product under vacuum 40-45° C. tillmoisture less than 2% to get the title compound (120 gm, purity 96%).

[0060] Step III

[0061] Preparation of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic Acidp-methoxy Benzyl Ester

[0062] To a suspension of PCl₅ (6.5 gm) in MDC (100 mL), pyridine (2.5gm) was added under ice cooling and the resulting suspension was stirredat this temperature for 30 minutes. To this7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (10 g) obtained in step II was added at below 0° C. Afterstirring at 0° C. for 90-120 min, the reaction mixture was cooled to−40° C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) wasadded below −10° C. for 30 minutes. After being stirred at 0° C. for 30minutes, the mixture was concentrated at 45° C. to get residue. Thisresidue was triturated with water (10 mL), EtOAc (40 mL) and isopropylether (IPE) (40 mL). The resulting precipitate was collected byfiltration, washed with IPE and dried to get the title compound (6.5 gm,>98%).

[0063] Step IV

[0064] Preparation of7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylicAcid p-methoxy Benzyl Ester

[0065] To a suspension of 7-amino-3-methoxymethyl-3-cephem-4-carboxylicacid p-methoxy benzyl ester (10 g), in MDC (50 mL, 5 volumes) obtainedin step III, BSA (10 g) was added at 30° C. for 30 minutes. Afterstirring at 30° C. for 50-60 minutes solution was cooled to −30° C.

[0066] Meanwhile in another flask to a suspension of PCl₅ (7.89 g) inMDC (50 mL, 5 volumes), 4-chloro-2(Z)-methoxyimino-3-oxo-butyric acidchloride (6.759) was added in four lots at 0 to −10° C. The resultingclear solution was added to the above silylated solution at −30 to −20°C. for 10-15 minutes time. After being stirred for another 15 minutes atsame temperature, chilled water (100 ml, 5 volumes) was added for 5minutes time. Concentrated the separated organic layer at 40-45° C. toget residue, which is triturated, with IPE (100 mL) to get the titlecompound (9.0 gm, 90%).

[0067] Step V

[0068] Preparation of7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3methoxymethyl-3-cephem-4-carboxylic Acid p-methoxy Benzyl Ester

[0069] To a mixture of THF (50 mL) and water (50 mL),7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylicacid p-methoxy benzyl ester (10 g) obtained in step IV was added at 30°C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30° C. wasadded and the resulting solution was stirred at 30° C. for 8-10 hours.After extracting the mixture with methylene dichloride (MDC) (100 mL),the resulting MDC layer was concentrated at 40° C. to get residue. Thisresidue was crystallized with MDC-IPE (1:5) mixture to get the titlecompound (9.5 g, 90%).

[0070] Step VI

[0071] Preparation of7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylicAcid (Cefpodoxime Acid)

[0072] Addition of trifluoro acetic acid (20.75 g) to a stirred solutionof phenol (125 mL) and7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylicacid p-methoxy benzyl ester obtained in step V (50 gm) at 40° C. over20-30 minutes. The reaction mixture was maintained at 40-45° C. for 2-4hours. Monitored the reaction by HPLC. After completion of the reaction,the reaction mixture was cooled to 25-30° C. and chilled water (250 mL),ethyl acetate (250 mL) was added and adjusted the pH to 7.3-7.5 with 25%Na₂CO₃ solution (90 mL) at 20° C. Stirred and separated the layers andextracted the aqueous layer with ethyl acetate (250 mL) and separatedthe layers. Adjusted the pH to 5.8 with 10% H₂SO₄ solution and chargedcarbon (10 gm), sodium dithionite (0.35 gm), and stirred the reactionmixture for 1 hour. Filtered and washed with water (50 mL). Adjusted thepH to 2.8 with 10% H₂SO₄ solution at 20-25° C. and stirred the reactionmixture at 5° C. for 3 hours. Filtered the product and washed withchilled acetone (−5 to −10° C., 100 mL) and suck dried to get the titlecompound (20 gm, purity>98%).

EXAMPLE-2

[0073] Step I

[0074] Preparation of7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylicAcid p-methoxy Benzyl Ester

[0075] To a suspension of PCl₅ (6.5 gm) in MDC (100 mL), pyridine (2.5gm) was added under ice cooling and the resulting suspension was stirredat this temperature for 30 minutes. To this7-phenylacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (10 g) obtained in step II was added at below 0° C. Afterstirring at 0° C. for 90-120 min, the reaction mixture was cooled to−40° C. To the cooled mixture pre-cooled methanol (30 mL, 3 volumes) wasadded below −10° C. for 30 minutes. After being stirred at 0° C. for 60minutes, the mixture temperature was taken to −20° C. and charged 20 mlof water below −10° C. The pH of the mass is adjusted to 4-4.5 by adding25% of sodium carbonate solution (40 ml) keeping the temperature below−5° C. The temperature of the reaction mass is raised to 30° C. in 30-40min. The layers were separated and to the organic layer was addedBis-(trimethylsilyl)urea (BSU) 8.5 g. The mass was stirred for 2-3 Hrsat 30° C.

[0076] The mixture was cooled to −30° C. Meanwhile in another flask to asuspension of PCl₅ (6.5 g) in MDC (50 mL, 5 volumes),4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid (5.6 g) was added in fourlots at 0 to −10° C. The resulting clear solution was added to the abovesilylated solution at −30 to −20° C. for 10-15 minutes time. After beingstirred for another 15 minutes at same temperature, chilled water (100m, 10 volumes) was added in 5-10 minutes. The temperature of the masswas raised to 30° C. over a period of 30-40 min. The layers wereseparated and the organic layer was treated with sodium carbonatesolution to bring its pH to 5.8-6.2. Again the layers were separated andthe organic layer was concentrated at 40-45° C. under vacuum to getresidue, which is triturated, with IPE (100 mL) to get the titlecompound (8.0 gm, purity>85%)

[0077] Step II

[0078] Preparation of7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylicAcid (Cefpodoxime Acid)

[0079] To a mixture of THF (50 mL) and water (50 mL),7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylicacid p-methoxy benzyl ester (10 g) obtained in step III was added at 30°C. To this thiourea (1.74 g) and sodium acetate (7.8 gm) at 30° C. wasadded and the resulting solution was stirred at 30° C. for 8-10 hours.After extracting the mixture with methylene dichloride (MDC) (100 mL),the resulting MDC layer was concentrated at 40° C. to get residue. Tothis residue was added phenol (25 mL) at 40-45° C. Trifluoro acetic acid(4.2 g) was added to the above mixture in 20-25 min at 40-45° C. Thereaction mass was stirred for 4-5 Hrs and finally poured into a mixtureof ethyl acetate (50 ml) and water (50 ml). The pH of the reaction masswas adjusted to 8.5 with 25% sodium carbonate solution at 30° C. Thelayers were separated. The aqueous layer was again washed with 50 ml ofethyl acetate. Finally the aqueous layer is treated with charcoal (1.0g), charcoal is filtered off and to the clear filtrate dilute sulfuricacid is added to bring the pH to 2.6-2.8. The mixture was cooled to 5°C. and product was collected by filtration and washed with acetone (3.0g, purity>98%).

1. A process for the preparation of cephalosporin antibiotics of theformula (I) or its esters, which form prodrug or a counter ion whichforms salt

wherein R₁ represents hydrogen, trityl, CH₃, CR_(a)R_(b)COOR_(c) whereR_(a) and R_(b) independently represent hydrogen or methyl and R_(c)represents hydrogen or (C₁-C₆)alkyl; R₂ represents hydrogen, CH₃,CH₂OCH₃, CH₂OCOCH₃, CH═CH₂, CH₂OCONH₂,

which comprises: (i) condensing the activated derivative of the formula(III)

where X represents halogen atom such as chlorine or bromine, withsilylated derivative of 7-amino cephalosporin of the formula (XIII)

wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl ordiphenylmethyl group and R² is as defined above in the presence of asolvent at a temperature in the range of −50° C. to 0° C. to produce acompound of formula (XIV),

where R¹ is as defined above, (ii) cyclising the compound of formula(XIV) with thiourea in the presence of solvent and sodium acetate atroom temperature to produce cephalosporin compound of the formula (XV)

wherein all symbols are as defined above, (iii) deesterifying thecompound of formula (XV) using anisole/trifluoroacetic acid,phenol/trifluoroacetic acid, formic acid in the presence or absence of asolvent at a temperature in the range of 0° C. to 60° C. to produce acompound of formula (I) and (iv) converting the compound of formula (I)to its pharmaceutically acceptable salt or its esters which formprodrug.
 2. The process as claimed in claim 1, wherein the solvent usedfor condensation is selected from dichloromethane, ethyl acetate,tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile,DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.3. The process as claimed in claim 1, wherein the activated derivativeof the compound of formula (III) is an acid halide, a mixed anhydride,an active ester or an active amide
 4. The process as claimed in claim 1,wherein solvent used for cyclisation in step (ii) is selected fromwater, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, dioxane, (C₁-C₃)alcohol or mixtures thereof. 5.The process as claimed in claim 1, wherein the solvent used fordeesterification in step (iii) is selected from dichloromethane ordichloroethane.
 6. The process as claimed in claim 1, wherein thepharmaceutically acceptable salt is sodium or hydrochloride.
 7. Theprocess as claimed in claim 1, wherein the prodrug ester is proxetil,axetil, hexetil or pivoxil.
 8. A process for the preparation of compoundof formula (XIII)

which comprises; (i) reacting the 7-aminocephalosporin derivative of theformula (XVI)

wherein R₃ represents hydrogen, (C₁-C₄)alkyl, substituted orunsubstituted phenyl or substituted or unsubstituted phenoxy with R₂—X,wherein X represents halogen atom and R₂ represents hydrogen, CH₃,CH₂OCH₃, CH₂OCOCH₃, CH═CH₂, CH₂OCONH₂,

in the presence in an organic solvent and a base at a temperature in therange of 0° C. to 30° C. to produce 7-aminocephalosporin derivative ofthe formula (XVII),

(ii) deacylating the compound formula (XVII) using PCl₅/POCl₃/pyridine,PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes in the presence of analcohol, at a temperature in the range of −40° C. to 0° C. to produce acompound of the formula (XIII) and (iii) isolating the compound offormula (XIII).
 9. The process as claimed in claim 8, wherein thesolvent used in step (i) is selected from tetrahydrofuran, acetone,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane,(C₁-C₃)alcohol or mixtures thereof
 10. The process as claimed in claim8, wherein the base used in step (i) is selected from sodium acetate,potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane(DABCO), 1,5-diaza-bicyclo[4,3,0]-non-5-ene (DBN),1,8-diazabicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.11. A process for the preparation of compound of formula (XIII)

wherein R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH═CH₂,CH₂OCONH₂,

which comprises; (i) acylating the 7-aminocephalosporin derivative ofthe formula (XVIII)

phenyl acetyl chloride to produce compound of formula (XIX)

in the presence of an organic solvent at a temperature in the range of−20° C. to 30° C., (ii) esterifying the compound of formula (XIX) usingan esterifying agent in the presence of a solvent and a base at atemperature in the range of 25° C. to 50° C. to produce a compound offormula (XX)

(iii) deacylating the compound of formula (XX) usingPCl₅/POCl₃/pyridine, PCl₅/pyridine, triphenyl phosphite/Cl₂ complexes inthe presence of an alcohol, at a temperature in the range of −40° C. to0° C. to produce a compound of the formula (XIII) and (iv) isolating thecompound of formula (XIII).
 12. The process as claimed in claim 11,wherein the solvent used in step (i) is selected from toluene, xylene,benzene, methylene dichloride, chloroform, ethyl acetate and the like.13. The process as claimed in claim 11, wherein the base used in step(ii) is selected from sodium carbonate, potassium carbonate, sodiumbicarbonate or potassium bicarbonate.
 14. The process as claimed inclaim 11, wherein the esterifying agent is selected from diphenyldiazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzylchloride.
 15. The process as claimed in claim 11, wherein the solventused for esterification is selected from methylene dichloride,chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone,acetonitrile, N,N-dimethylformamide, dimethyl sulfoxideN,N-dimethylacetamide, dioxane, (C₁-C₃)alcohol or mixtures thereof. 16.A process for the preparation of compound of formula (XIII)

wherein R₂ represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH═CH₂,CH₂OCONH₂,

comprising esterifying the compound of the formula (XVIII)

using an esterifying agent in the presence of a solvent and base. 17.The process as claimed in claim 16, wherein the solvent used is selectedfrom tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, dioxane, (C₁-C₃)alcohol or mixtures thereof. 18.The process as claimed in claim 16, wherein the base used is selectedfrom sodium acetate, potassium carbonate, triethylamine,1,4-diazabicyclo-[2,2,2]-octane (DABCO),1,5-diazabicyclo[4,3,0]-non-5-ene (DBN),1,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate.19. An intermediate of the formula (XIV)

wherein X represents halogen atom such as chlorine or bromine; Rrepresents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R₂represents hydrogen, CH₃, CH₂OCH₃, CH₂OCOCH₃, CH═CH₂, CH₂OCONH₂,